A Novel Competing Endogenous RNA Network Reveals Potential Mechanisms and Biomarkers of Chemoresistance in Lung Adenocarcinoma

Platinum resistance is a common cause of chemotherapy failure in lung adenocarcinoma (LUAD). Competing endogenous RNAs (ceRNAs), which function by competitively binding to miRNAs, can influence drug response. However, the regulatory mechanisms of ceRNAs underlying chemoresistance in LUAD remain largely unknown. Here, we proposed an integrated pipeline combining limma algorithm, miRNA binding prediction algorithm, expression correlation model and experimental support to identify functional lncRNA-miRNA-mRNA competing triplets associated with resistance, which showed variable competing patterns between resistant and sensitive cells. We found that a minority of altered ceRNAs overlapped in multiple types of cisplatin-resistant LUAD cell lines and were involved in biological processes known to mediate cancer drug response. We identified them as core resistance factors, forming a novel lncRNA-mediated resistance-related ceRNA network, which indicated a potential mechanism. Single-cell analysis revealed that these resistance-related ceRNAs regulated the functional states of LUAD cells, and survival analysis showed that they contributed to the prognosis of LUAD patients. The lncRNA regulators H19 and MIR193BHG were found to correlate with cisplatin activity in LUAD cell lines, and dysregulation of their expression triggered disorders of cisplatin response-related functions through multiple ceRNA regulatory axes in this network, suggesting them as potential resistance biomarkers and therapeutic targets. In summary, the integrated pipeline and the resulting data serve as a valuable resource for understanding the ceRNA mechanisms of chemoresistance and improving chemotherapy response.